Background

West syndrome is a severe epilepsy syndrome composed of the triad of infantile spasms, an interictal electroencephalogram (EEG) pattern termed hypsarrhythmia, and mental retardation. The International League Against Epilepsy's (ILAE) revised classification and terminology of seizures and epilepsies, published in 2010, designates West syndrome as an electroclinical syndrome with onset in infancy, and epileptic spasms as a type of seizure.
[1] (See Presentation and Workup.)

West syndrome is an age-dependent expression of a damaged brain, and most patients with infantile spasms have some degree of developmental delay. The term infantile spasm has been used to describe the seizure type, the epilepsy syndrome, or both. In this article, the term infantile spasm is synonymous with West syndrome. (See Prognosis and Presentation.)

The syndrome's namesake, Dr W J West, gave the first detailed description of infantile spasms, which occurred in his own child.
[2] In a letter to the editor of The Lancet in 1841, West described the events as "bobbings" that "cause a complete heaving of the head forward towards his knees, and then immediately relaxing into the upright position … [T]hese bowings and relaxings would be repeated alternately at intervals of a few seconds, and repeated from 10 to 20 or more times at each attack, which would not continue more than 2 or 3 minutes; he sometimes has 2, 3 or more attacks in the day."
[3]

This detailed clinical description was followed approximately 100 years later by the report of the typical interictal EEG pattern termed hypsarrhythmia. (See Workup.)

The eponym West syndrome was created in the early 1960s by Drs. Gastaut, Poirier, and Pampiglione.

Differentials

Conditions to consider in the differential diagnosis of West syndrome include the following:

Etiology

Infantile spasms are believed to reflect abnormal interactions between the cortex and brainstem structures. Focal lesions early in life may secondarily affect other sites in the brain, and hypsarrhythmia may represent this abnormal activity arising from multiple brain sites. The frequent onset of infantile spasms in infancy suggests that an immature central nervous system (CNS) may be important in the syndrome’s pathogenesis.

The brain-adrenal axis also may be involved. One theory states that the effect of different stressors in the immature brain produces an abnormal, excessive secretion of corticotropin-releasing hormone (CRH), causing spasms.
[4] The clinical response to adrenocorticotropic hormone (ACTH) and glucocorticoids can be explained by the suppression of CRH production.

An existing animal model of infantile spasm may provide better insight into the pathogenesis of this disorder. The model uses a sodium channel blocker, tetrodotoxin (TTX), that is infused into the hippocampus of rodents. This infusion has produced clinical spasms in rats with electrographic findings similar to those seen in human infantile spasms.
[5]

Infantile spasms can be classified according to their suspected etiology as symptomatic, cryptogenic, or idiopathic.

Symptomatic

Patients are diagnosed with symptomatic infantile spasms if an identifiable factor is responsible for the syndrome. Virtually any disorder that can produce brain damage can be associated with infantile spasms. The list of etiologies can be subdivided into prenatal disorders, perinatal disorders, and postnatal disorders.

Prenatal disorders associated with infantile spasms include the following:

Hydrocephalus

Hydranencephaly

Migrational disorders such as schizencephaly polymicrogyria

Sturge-Weber syndrome

Incontinentia pigmenti

Tuberous sclerosis

Trisomy 21

Hypoxic-ischemic encephalopathy

Congenital infections

Trauma

Perinatal disorders giving rise to infantile spasms include the following:

Hypoxic-ischemic encephalopathy

Meningitis

Encephalitis

Trauma

Intracranial hemorrhages

Postnatal disorders associated with infantile spasms include the following:

Evaluating children with infantile spasms for possible tuberous sclerosis is critical, as this is the single most common disorder, accounting for 10-30% of prenatal cases of infantile spasm. Tuberosis sclerosis is an autosomally dominant inherited disease with variable manifestations, including cardiac tumors, kidney tumors, cutaneous malformations such as ash-leaf hypopigmented lesions, and seizures.

Of patients with infantile spasms, 70-75% have symptomatic epilepsy; this percentage depends on the degree of sophistication of diagnostic studies. (The development of more exquisite neurodiagnostic techniques is expected to alter the relative proportion of symptomatic, cryptogenic, and idiopathic cases that has been reported.)

Cryptogenic

Patients have cryptogenic infantile spasms if no cause is identified but a cause is suspected and the epilepsy is presumed to be symptomatic.

The proportion of cryptogenic cases varies from 8-42%. This wide range may be related to variations in the definition of the term cryptogenic and the age of patients at diagnosis, since assessment of developmental level in early infancy is difficult.

Idiopathic

Patients may be considered to have idiopathic infantile spasms if normal psychomotor development occurs prior to the onset of symptoms, no underlying disorders or definite presumptive causes are present, and no neurologic or neuroradiologic abnormalities exist. Some investigators use the terms idiopathic and cryptogenic interchangeably. The percentage of idiopathic cases reportedly is 9-14%.

Genetics

There has been an increased understanding of the role of genetic defects in the etiology of infantile spasms, such that there are panels of genetic mutations tha are commercially available for testing. In addition to the genetic mutations in TSC1 and TSC2, which cause tuberous sclerosis, specific genetic defects have been identified in many patients with early onset of infantile spasms, including mutations in the gene ARX on the short arm of chromosome X, which is associated with a wide variety of structural brain abnormalities, and a mutation in the cyclin-dependent kinase-like protein 5 (CDKL5).

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Epidemiology

Occurrence in the United States

Infantile spasm constitutes 2% of childhood epilepsies but 25% of epilepsy with onset in the first year of life. The rate of infantile spasm is estimated to be 2.5-6.0 cases per 10,000 live births. Its prevalence rate is 1.5-2.0 cases per 10,000 children aged 10 years or younger.

International occurrence

Infantile spasm occurs in 0.05 (Estonia) to 0.41 (Oulu, Finland) of 1000 live births and in 1.4% (Estonia), 4.2% (Odense, Denmark), and 7.6% (Tampere, Finland) of children with epilepsy.

Sex- and age-related demographics

Although males are affected by infantile spasm slightly more often than females, no significant gender difference is noted in infantile spasm. Ninety percent of infantile spasms begin in infants younger than 12 months. Peak onset is at age 4-6 months.
[6]

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Prognosis

The long-term overall prognosis for patients with infantile spasm is poor and is related directly to the condition’s etiology.
[7, 8] Infants with idiopathic infantile spasms have a better prognosis than do infants with symptomatic infantile spasms. Only 14% of infants with symptomatic West syndrome have normal or borderline-normal cognitive development, compared with 28-50% of infants with idiopathic infantile spasms. Mental retardation is severe in 70% of patients, often with psychiatric problems such as autistic features or hyperactivity.

Infrequently, spasms may persist in adulthood. It has been found that 50-70% of patients develop other seizure types and that 18-50% of patients will develop Lennox-Gastaut syndrome or some other form of symptomatic generalized epilepsy.
[6, 9]

Subsets of patients among the symptomatic infantile spasms group seem to have a better prognosis. A retrospective study of 17 children with trisomy 21 and infantile spasms found that 13 of 16 survivors were seizure free for more than 1 year and that 10 patients were no longer taking anticonvulsants.

A study of 15 children with neurofibromatosis type 1 and infantile spasms also reported a relatively benign seizure and cognitive outcome.

Favorable prognostic factors also include the following:

Cryptogenic or idiopathic etiology

Age of onset of over 4 months

Absence of atypical spasms and partial seizures

Absence of asymmetrical EEG abnormalities

Short time from onset to treatment

Early, sustained response to treatment

Infants with symptomatic infantile spasms have been shown to be at higher risk for the development of autism spectrum disorders, compared with those infants with cryptogenic or idiopathic spasms.
[10, 11]

Mortality

The premature death rate for infantile spasm ranges from 5-31%. The upper limit comes from a study of 214 Finnish children with a history of infantile spasms who were followed for a mean period of 25 years (range, 20-30 y). Most of the deaths (61%) occurred at or before age 10 years, while only 10% occurred after age 20 years.

Saemundsen E, Ludvigsson P, Rafnsson V. Risk of autism spectrum disorders after infantile spasms: a population-based study nested in a cohort with seizures in the first year of life. Epilepsia. 2008 Nov. 49(11):1865-70. [Medline].

Disclosure: Received consulting fee from Eisai, ucb Pharma, Supernus, SK Life Science, Claritas, and Sunovion for consulting; Received royalty from AssureRx for license.

Coauthor(s)

Diego A Morita, MD Assistant Professor of Pediatrics and Neurology, Department of Pediatrics, Division of Neurology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Biomarin; Supernus<br/>Received income in an amount equal to or greater than $250 from: Biomarin; Supernus; American Board of Pediatrics.

Acknowledgements

Robert J Baumann, MD Professor of Neurology and Pediatrics, Department of Neurology, University of Kentucky College of Medicine